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Comparison of suspected Lynch syndrome patients carrying BRCA and BRCA-like variants with Lynch syndrome probands: Phenotypic characteristics and pedigree analyses.

ABSTRACT: BACKGROUND:Colorectal cancer (CRC) patients diagnosed with Lynch syndrome (LS) are recommended genetic testing. Increasing numbers of germline variants involved in homologous recombination have been identified in suspected LS patients. This study compared phenotypic the characteristics of suspected LS patients carrying BRCA and BRCA-like variants with those of LS patients. METHODS:Forty-two patients carrying pathogenic variants of DNA mismatch repair (MMR) genes (MMR group), 9 carrying BRCA variants, and 11 carrying BRCA-like variants (BRCA/BRCA-like group) who met LS clinical criteria were enrolled in this study. Clinical characteristics, pedigrees, and survival rates were compared and BRCA variants were analyzed. RESULTS:The earliest CRC-onset age and tumor differentiation were higher in the BRCA/BRCA-like group than in the MMR group. Metachronous CRCs were more numerous in the MMR group, resulting in a higher progression-free survival rate in the BRCA/BRCA-like group. Extra-colorectal cancers were more frequently observed in the BRCA/BRCA-like group. BRCA2 and BRCA1 variants were clustered in exons 11 and 4/7, respectively. CONCLUSION:BRCA and BRCA-like variants in CRC patients with LS showed moderate penetrance. BRCA/BRCA-like variant carriers had a higher risk for extra-colorectal cancers. Surveillance of susceptible organs other than the intestine should be performed for probands and affected family members.

SUBMITTER: Xu Y

PROVIDER: S-EPMC7434599 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Comparison of suspected Lynch syndrome patients carrying BRCA and BRCA-like variants with Lynch syndrome probands: Phenotypic characteristics and pedigree analyses.

Xu Yun Y Li Cong C Wang Zhimin Z Liu Fangqi F Xu Ye Y

Molecular genetics & genomic medicine 20200616 8

<h4>Background</h4>Colorectal cancer (CRC) patients diagnosed with Lynch syndrome (LS) are recommended genetic testing. Increasing numbers of germline variants involved in homologous recombination have been identified in suspected LS patients. This study compared phenotypic the characteristics of suspected LS patients carrying BRCA and BRCA-like variants with those of LS patients.<h4>Methods</h4>Forty-two patients carrying pathogenic variants of DNA mismatch repair (MMR) genes (MMR group), 9 car ...[more]

PMID: 32548945

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Project description:ObjectiveWhole-exon sequencing (WES) is a commercially available tool for hereditary disease testing. However, little is known about hereditary upper-tract urothelial carcinoma (UTUC) in the Chinese population. This study aims to investigate the prevalence of Lynch syndrome (LS) in UTUC patients with high-risk features and identify the germline mutations of genetic predisposition gene mutations in those patients.MethodsIn total, 354 consecutive UTUC patients undergoing surgery were universally recruited, of whom 108 patients under 60 years old or with a personal/family history of cancer underwent universal immunohistochemistry staining to detect the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Patients with deficient or weak MMR protein staining or meeting the Amsterdam II criterion were defined as suspected LS patients, who further experienced microsatellite instability (MSI) (BAT25, BAT26, BAT40, D2S123, D5S346, D17S250) detection and performed WES analysis to explore germline pathogenic/likely pathogenic (P/LP) alterations.ResultsOf 108 patients, 90 (83.3%) cases were included due to younger than 60 years, and 18 cases due to personal/family history. IHC staining identified 21 patients with deficient MMR protein staining and 15 cases with weak MMR protein staining. Three cases met the Amsterdam II criterion but with proficient MMR protein staining. Finally, WES analysis was performed in 38 suspected LS patients and P/LP germline mutations were identified in 22 individuals. Genetic testing confirmed 5 LS cases, including 3 cases with novel mutations. MSI-harboring tumor was discovered in 4 LS cases, one of whom had weak MMR protein staining. Germline P/LP variants in DNA damage repair genes were found in 11 cases. In addition, we found that 11 patients had high- or moderate- penetrance P/LP mutations other than MMR genes. The common P/LP variants in high- or moderate-penetrance genes were 4 in ATM, 3 in MSH6 and KIT, and 2 in APC, NF1 and DICER.ConclusionsWe identified approximately 11% of UTUC cases as suspected LS and at least 1.4% patients with confirmed LS-associated UTUC. In addition, broader germline genetic testing could be considered to screen for cancer severity in hereditary UTUC patients.

Project description:In this study, we compared the molecular, clinical, and pathological characteristics, as well as pedigrees, between patients with Lynch-like syndrome (LLS) and confirmed Lynch syndrome (LS) to develop appropriate management strategies for patients with LLS and their affected family members. Between June 2008 and September 2018, 81 patients with LLS and 47 patients with LS who developed colorectal cancer (CRC) were enrolled in this study. Multigene panel testing included 139 genes and was performed for all patients. The variants identified in each group were described, and clinicopathological characteristics and pedigrees were compared between the two groups. In the LLS group, a total of 52 variants were detected in 44 (54.3%) patients. Among the 52 variants, 17 were variants of unknown significance in mismatch repair genes, and the other most frequently mutated genes were MUYTH, POLE, BRCA2, and GJB2. The proportion of early-onset patients was significantly higher among the LS probands than among the LLS probands (74.5 and 53.1%, respectively; ?2 = 5.712, P = 0.017). On the other hand, the proportion of primary CRC developed in the rectum was higher in the LLS group than in the LS group (25.9 and 10.6%, respectively; ?2 = 2.358, P = 0.046). There were no significant differences in the occurrence of metachronous CRC (P = 0.632) and extra-colorectal cancer (extra-CRC) (P = 0.145) between the two groups. However, analysis of pedigrees showed that more patients developed CRC in the LS families (P = 0.013), whereas more patients with extra-CRC were observed in the LLS families (P = 0.045). A higher prevalence of male patients was observed in the LLS families (P = 0.036). In conclusion, LLS should be classified as a mixed entity, containing cases of LS, other hereditary cancer syndromes, and sporadic CRC. The high risks of CRC and extra-CRCs, which were found in this study, suggest tailored management policy and surveillance should be formulated based on individual and family risk. The surveillance regimen can be based on the presence of confirmed pathogenic/likely pathogenic germline variant(s) and family history.

Dataset Information

Comparison of suspected Lynch syndrome patients carrying BRCA and BRCA-like variants with Lynch syndrome probands: Phenotypic characteristics and pedigree analyses.

Publications

Comparison of suspected Lynch syndrome patients carrying BRCA and BRCA-like variants with Lynch syndrome probands: Phenotypic characteristics and pedigree analyses.

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